This invention relates to a clear, stable novel pharmaceutical preparation of selective cyclooxygeiase II inhibitors (COX 2) inhibitors preferably in the parenteral form for the treatment of pain and inflammatory conditions arising because of cyclooxygenase-2 activity.
Selective COX 2 inhibitors like Celecoxib, Rofecoxib and their analogs have been widely indicated for the treatment of mucoskeletal disorders such as rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and for the management of acute pain. They have also been indicated for primary treatment of dysmenorrhea. Chronic treatment of patients with Rofecoxib and Celecoxib has been effective in suppressing the inflammation without causing gastric toxicity which is normally associated with non selective NSAID (Simon et al, 1998, 1999; Bensen et al 1999 Emery et al 1999; Howaky et al 2000, Schintzer et al 1999; Ehlidrich et al 1999; Laine eta al 1999 through Goodman and Gilman""s The pharmacological basis of therapeutics 10th edition, McGraw Hill Medical Publication Division 2001).
WO 0145705 and WO 0145706 teaches preparation of oral formulations of celecoxib.
WO 0069434 and WO 0032189 discloses solid dosage forms of COX2 inhibitors modified by mixing the same with excipients to achieve a metter availability of the drug as a oral dosage formulation.
Publication WO 0048583 is directed to again an oral dosage formulation of Rofecoxib with 5HT antigonists.
WO 0032189 published yet further celecoxib composition for oral consumption as a sustained release dosage form for the treatment of cycloxygenase mediated disorders.
Thus all the presently available selective COX 2 inhibitors are either prepared as oral tablets and/or oral liquid suspensions. Although easy to administer, oral dosage forms delay the onset of the desired pharmacological action due to the amount of time this route of administration takes to achieve the required plasma concentrations of the drug. As a result of this, the selective COX 2 inhibitors have a significant lag time before the onset of therapeutic effect. Additionally, the intake of food even further influences this drug absorption and hence the time taken for the onset of action. It has also been reported that some of these selective COX 2 inhibitors decrease the therapeutic concentration by a further 20% when taken along with Antacids.
Due to these above limitations, selective COX 2 inhibitors in parenteral form capable of instant therapeutic action are extremely desirable. In order to prepare parenteral formulations of these class of compounds, a suitable carrier/vehicle is required in which these drugs are soluble. Obviously, this carrier/vehicle need to be safe and non-toxic. Due to the physiochemical properties of these groups of compounds, selective COX 2 inhibitors like Celecoxib, Rofecoxib, Valdecoxib, Itacoxib and Deracoxib are poorly soluble in water hence presenting a difficulty in formulating these drugs in the parenteral form.
Attempts to provide COX-2 Inhibitors like Celecoxib and Rofecoxib or analogs in parenteral form using various solvents viz., Alcohols, Dimethyl Sulphoxide, Propylene Glycol and Glycerin were found to be unsuccessful either due to problems of solubility or that when these drugs dissolve in solvents like Isopropenol Acid mixture, Dimethyl Sulphoxide and Propylene Glycol the concentration range for the therapeutic administration of the above drugs through intramuscular route does not permit the above solvent usage as they are found to be toxic.
Due to such problems it has not been possible to have injectable formulation of Celecoxib, Rofecoxib, Valdecoxib, Etoricoxib or Deracoxib. The only injection available is in the form of Paracoxib which is a pro-drug of Valdecoxib and is available as a sodium salt. Paracoxib when administered parentally, is hydrolysed to Valdecoxib after reaching the blood stream.
It is known that paranteral administration is always beneficial for quick onset of action for the anti-inflammatory/analgesic activity. This is because quick action on body when drug is administered, concentration of the drug has to reach maximum level in the blood to achieve the therapeutic effect and this is achievable by injectable preparation than by oral preparation. Oral preparations when administered takes concentration time to reach blood level as it has to undergo first-pass metabolism.
Thus although there has been a need in the art for injectable forms of COX-2 inhibitors for direct parenteral administration it could not be achieved because of the above discussed limitation of solubility and problems of toxicity.
It is thus the basic object of the present invention to provide a stable pharmaceutical preparation of selective COX 2 inhibitors such as Rofecoxib or Celecoxib or analogs preferably in parenteral form capable of instant therapeutic action which would avoid the above discussed limitations of obtaining COX 2 inhibitors in parenteral form.
Another object is directed to provide injectable pharmaceutical preparation of selective COX 2 inhibitor such as Rofecoxib or Celecoxib or analogs preferably in parenteral form which would be simple and cost-effective to obtain.
Yet further object of the present invention is directed to provide injectable pharmaceutical preparation of selective COX 2 inhibitor such as Rofecoxib or Celecoxib or analogs preferably in parenteral form which would be stable, clear, limpid and easily administrable intramuscularly and would be safe having instant therapeutic activity vis-{dot over (a)}-vis the presently available oral tablets/liquid formulations of COX 2 inhibitors.
Yet further object of the present invention is directed to provide pharmaceutical preparation of selective COX 2 inhibitor such as Rofecoxib or Celecoxib or analogs in gel form.
It has been found by way of the present invention that injectable formulations of COX 2 inhibitors can be obtained of COX 2 inhibitors only when dissolved in a selective isosorbide type solvent of following general formula I. 
where R1 and R are hydrogen or alkyl chains containing 1-3 carbons or acetate group.
Thus according to one aspect of the present invention there is provided a stable pharmaceutical preparation such as for parenteral administration of COX 2 inhibitors comprising of selective active COX 2 inhibitors selected from Celecoxib, Rofecoxib and their analogs dissolved in a selective isosorbide type solvent of following general formula I. 
where R1 and R are hydrogen or alkyl chains containing 1-3 carbons or acetate group.
The formulation of the invention above can optionally contain water and/or one or more antioxidants.
This solution is clear and limpid and can be easily administered intramuscularly with the desired therapeutic dose. This formulation is stable, safe and effective. In certain cases, it is even better than the presently widely used anti-inflammatory drugs like Diclofenac sodium injection administered by intramuscular route.
In accordance with one embodiment the formulation of the selective active Rofecoxib is prepared by selectively dissolving Rofecoxib in Isosorbide type solvent with or without water.
In accordance with another embodiment the formulation of the selective Celecoxib is prepared by selectively dissolving Celecoxib in Isosorbide type solvent preferably containing antioxidants. The addition of an antioxidant like alpha tocopherol and/or its derivatives enhances the stability of the Celecoxib preparation.
In acordance with a preferred aspect of the invention the pharmaceutical preparation comprising the injection of Celecoxib can be prepared in the strength of 1 mg/ml to 500 mg/ml in said solvent DMI.
In acordance with another preferred aspect of the invention the pharmaceutical preparation comprising the injection of Rofecoxib can be prepared in the strength of 1 mg/ml to 50 mg/ml in said solvent DMI.
In both said injectable forms of the pharmaceutical preparation of the invention optionally anti-oxidants like Sodium bisulphate or Vit.E can be incorporated.
In accordance with yet another aspect of the invention the Celecoxib and Rofecoxib preparations can be provided in the form of Gel using the same solvent in the strength of 1% to 4% for local applications with or without other ingredients such as carbomer derivatives, HPMC (hydroxy propyl methyl cellulose), gelatine, sodium CMC, water and flavouring agent.
In accordance with another aspect the present invention also relates to process for manufacturing of the parenteral preparation of COX 2 inhibitor preferably for parenteral administration comprising
i) selectively providing a COX 2 inhibitor selected from Rofecoxib, celecoxib and analogous thereof; and
ii) dissolving the said selected COX 2 in a selective isosorbide type solvent of general formula I 
where R1 and R are hydrogen or lower alkyl chains containing 1-3 carbons or acetate groups and optionally water/and one or more antioxidants.
The present invention further relates to the use of the above described parenteral preparation for the treatment of pathological conditions associated with rheumatoid arthritis and osteoarthritis and for the treatment of primary dysmenorrhea in which composition comprising of the selective actives Celecoxib, Rofecoxib, their analogs and compound of general formula I. 
wherein R1 and R are hydrogen or lower alkyl chains containing 1-3 carbons or acetate and optionally water/and one or more antioxidants.
The compound of Formulae I is preferably 2,5-di-O-methyl-1, 4:3,6 dianhydro-D-glucitol.
The compounds represented by the general formula I are selectively identified as an excellent solvent for Celecoxib, Rofecoxib and their analogs. It has been surprisingly found that the solubility of Celecoxib and Rofecoxib in the selective compounds of general formula I, avoid the problems of preparation of liquid/parenteral formulations of COX 2 inhibitors. The parenteral formulation prepared by dissolving Celecoxib (with and without the presence of an antioxidant) and Rofecoxib in compounds represented by formula I can be safely used for the treatment of inflammation and the pathological condition associated and mediated because of Cyclooxygenase II and for its inhibition.
Addition of upto 20% water to the above mentioned parenteral preparation of Rofecoxib does not alter the physical or chemical stability of the preparation.
Also, it was observed that the addition of an antioxidant like alpha tocopherol (upto 0.1%) to the above mentioned parenteral preparation of Celecoxib results in a very stable solution with no change in characteristic over extended period of time.